Vancomycin is an antibiotic which was initially discovered in the 1950's, see U.S. Pat. No. 3,067,099. It is usually reserved for use in the treatment of severe gram positive infections such as those caused by Staphylococcus aureus and when traditional antibiotics have failed. Over the years, there have been several proposals for improving one or more attributes of vancomycin, usually by continuous infusion. In another example, prodrugs of vancomycin have been proposed as a way of increasing the solubility and circulating life of the drug.
Prodrugs include chemical derivatives of a biologically-active parent compound which, upon administration, will eventually liberate the active parent compound in vivo. The use of prodrugs allows the artisan to modify one or more properties such as the onset and/or duration of action of a biologically-active compound in vivo. Prodrugs are often biologically inert or substantially inactive forms of the active compound. The rate of release of the active drug is influenced by several factors including the rate of hydrolysis of the linker which joins the parent biologically active compound to the prodrug carrier.
Polymer conjugates of vancomycin have also been proposed as potential prodrugs. For example, commonly-assigned U.S. Pat. No. 6,180,095 discloses benzyl elimination (BE) systems as part of a tripartate polymer-based prodrug platform. These BE prodrug systems are designed inter alia to releasably attach polymers such as polyethylene glycol (hereinafter PEG) to hydroxyl or amine residues on small molecules. After administration to a patient, the prodrugs break down in a predictable fashion. First, the polymer portion hydrolyzes at a predictable, predetermined rate due to the presence of selected bifunctional linkers which contain the desired “trigger”. Once the polymer portion has been hydrolyzed, the BE system is initiated or triggered by having a free phenol or aniline derivative and rapidly releases the parent compound. Commonly assigned U.S. Pat. Nos. 5,965,119 and 6,303,569 disclose related tripartate prodrug systems containing trimethyl lock triggers. The disclosure of each of the above-mentioned commonly-assigned patents is incorporated herein by reference.
In spite of the fact that vancomycin is listed among the various biologically active compounds having an available amino group for attachment of the prodrug platform in each of the foregoing commonly-assigned patents, further advances have been sought to refine and improve prodrugs of vancomycin. For example, unlike many biologically active compounds, vancomycin has two amino groups, i.e. the sugar amino (V3) and N-methyl amino (Xi), which are available for polymeric substitution. Thus, control of the substitution reactions involving these amino groups is desirable. It has now been determined that it would be beneficial under certain circumstances to provide vancomycin polymer prodrugs which have the polymer attached substantially exclusively on one of the amino groups. It has further been discovered that other and further advantages are realized when a polymer is attached to both of the vancomycin amino groups. The present invention addresses such needs.